N6-Methyladenine DNA Modification in the Human Genome

Chuan-Le Xiao; Song Zhu; Minghui He; De Chen; Qian Zhang; Ying Chen; Guoliang Yu; Jinbao Liu; Shang-Qian Xie; Feng Luo; Zhe Liang; De-Peng Wang; Xiao-Chen Bo; Xiao-Feng Gu; Kai Wang; Guang-Rong Yan

doi:10.1016/j.molcel.2018.06.015

N⁶-Methyladenine DNA Modification in the Human Genome

Mol Cell. 2018 Jul 19;71(2):306-318.e7. doi: 10.1016/j.molcel.2018.06.015. Epub 2018 Jul 12.

Authors

Chuan-Le Xiao¹, Song Zhu², Minghui He³, De Chen², Qian Zhang⁴, Ying Chen⁵, Guoliang Yu⁶, Jinbao Liu⁷, Shang-Qian Xie⁵, Feng Luo⁸, Zhe Liang⁹, De-Peng Wang⁶, Xiao-Chen Bo¹⁰, Xiao-Feng Gu¹¹, Kai Wang¹², Guang-Rong Yan¹³

Affiliations

¹ Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; College of Plant Protection, Hunan Agricultural University, Changsha 410128, China.
² Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
³ CookGene Biosciences Center, Guangzhou 510320, China.
⁴ Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
⁵ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
⁶ Grandomics Biosciences, Beijing 102206, China.
⁷ Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
⁸ School of Computing, Clemson University, Clemson, SC 29634-0974, USA.
⁹ Department of Biological Sciences, National University of Singapore, 117543 Singapore, Singapore.
¹⁰ Dapartment of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: boxc@bmi.ac.cn.
¹¹ Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China. Electronic address: guxiaofeng@caas.cn.
¹² Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: wangk@email.chop.edu.
¹³ Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: jxygr007@yahoo.com.

PMID: 30017583
DOI: 10.1016/j.molcel.2018.06.015

Abstract

DNA N⁶-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in the human genome, and we cataloged 881,240 6mA sites accounting for ∼0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. DNA 6mA and N⁶-demethyladenine modification in the human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompanied by decreased N6AMT1 and increased ALKBH1 levels, and downregulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis.

Keywords: 6mA; cancer; demethylase; human genome; m6A; methylation; methyltransferase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives*
Adenine / metabolism
AlkB Homolog 1, Histone H2a Dioxygenase / genetics
AlkB Homolog 1, Histone H2a Dioxygenase / metabolism*
Animals
Carcinogenesis / genetics
DNA / genetics
DNA Methylation
Genome, Human*
Heterografts
Humans
Mice
Mice, Nude
Site-Specific DNA-Methyltransferase (Adenine-Specific) / genetics
Site-Specific DNA-Methyltransferase (Adenine-Specific) / metabolism*

Substances

DNA
ALKBH1 protein, human
AlkB Homolog 1, Histone H2a Dioxygenase
N6AMT1 protein, human
Site-Specific DNA-Methyltransferase (Adenine-Specific)
Adenine
6-methyladenine